On July 7, the research group of Assistant Professor Hiroaki Takeuchi and Professor Shoji Yamaoka of the Department of Virus Control, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University collaborated with Kyoto University, National Institute of Infectious Diseases, and Shionogi Pharmaceutical Co., Ltd. It was announced that the cause of the collapse of the virus core structure in AIDS virus-infected cells was found to be the core structure phosphorylation of the intracellular phosphorylating enzyme MELK.
The human immunodeficiency virus (HIV-1), which is the causative virus of AIDS, has RNA as a gene, and synthesizes DNA using RNA as a template in the infection target cell by a process called reverse transcription, and viral DNA is added to the gene of the infected cell. Incorporate.In addition, when HIV-1 invades the infection target cell, it releases the core structure contained in the virus particles into the cell. It has long been known that the establishment of HIV infection requires "spatiotemporal" coordination between this viral DNA synthesis step and core structure collapse, but concretely controlling the timing of core structure collapse. Mechanism was unknown.
The research group conducted genome-wide RNA interference screening using CD1-positive T lymphocytes, which are one of the HIV-4 infection target cells, and found the phosphorylating enzyme MELK as a host intracellular factor that controls HIV-1 infection.Analysis of MELK's ability to control HIV-1 infection revealed that when HIV-4 infects CD1-positive T lymphocytes that suppress MELK expression, the timing of viral core structure disruption is delayed, and the viral DNA synthesis step is inhibited. It turned out that it would be done.
It was also revealed that MELK controls the decay of the HIV-1 core structure by stepwise phosphorylating specific amino acid residues of the HIV-1 capsid protein (HIV-1 CA) that forms the core structure. bottom.
This result clarified the mechanism of controlling the decay of the HIV-1 core structure and identified the host-side factors essential for HIV-1 infection.In addition, since the discovered host protein was a kinase, it is expected to be applied to the development of new AIDS treatment methods targeting host-side infection control factors rather than virus-derived enzyme proteins that are easily mutated.
Paper information:[PLOS Pathogens] Phosphorylation of the HIV-1 capsid by MELK triggers uncoating to promote viral cDNA synthesis
